Human transcription factor combinations mapped by footprinting with deaminase

An individual's somatic cells have the same genome but exhibit cell-type-specific transcriptome regulated by a combination of transcription factors (TFs) for each gene. Mapping of TF sites on the human genome is critically important for understanding functional genomics. Here we report a novel technique to measure human TFs' binding sites genome-wide with single-base resolution by footprinting with deaminase (FOODIE). Single-molecule sequencing reads from thousands of cells after in situ deamination yielded site-specific TF binding fractions and the cooperativity among adjacent TFs. In a human lymphoblastoid cell line, we found that, genes in a correlated gene module (CGM) share TF(s) in their cis-regulatory elements to facilitate a particular biological function. Finally, single-cell resolved experiments (scFOODIE) allow cell-type-specific TF footprinting in heterogeneous brain tissues.